The invention relates to a process for the production of diethylenetriaminepentacarboxylic acid tetraesters of terminal carboxylic acids as well as the use of compounds, produced by the described process, for the production of agents for NMR, x-ray and radiodiagnosis as well as radiotherapy.
Diethylenetriaminepentaacetic acid (DTPA) and derivatives of this compound are widely used in medicine and technology, both in free form and in the form of their complex compounds. In EP 71564 B1, i.a., the meglumine salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid (DTPA) is described as a contrast medium for NMR tomography. A preparation which contains this complex was approved worldwide under the name Magnevist.RTM. as the first NMR contrast medium. After intravenous administration, this contrast medium spreads extracellularly and is excreted renally by glomerular secretion. A passage of intact cell membranes is practically not observed. Magnevist.RTM. is especially well-suited for the visualization of pathological areas (e.g., inflammations, tumors).
In the past, there have been many attempts to link DTPA with functional radicals which exhibit an organ or cell specificity to achieve in this way a contrast medium concentration in certain types of tissue.
A DTPA derivative, which is suitable to be used as starting substance for the regioselective linkage of the central carboxylic acid of the DTPA derivative to an amine-containing radical, which has the above-mentioned properties, was described by Rapoport (J. Org. Chem., 58, 1151 (1993)). But the process for the production of this tetraester indicated in this bibliographic reference is affected by the drawback that it uses an amino acid as starting material. Thus, the possible substitution models of the products of this process are limited to the substitution models of the available amino acids. There is therefore a need for a process which avoids this drawback and allows the production of compounds with substituents, which do not occur in amino acids. The object of the invention thus is to make available such a process. The achievement of this object is performed by the object characterized in the claims.
It has been found that the process for the production of diethylenetriaminepentacarboxylic acid tetraesters of general formula (I) ##STR2## in which R.sup.1 stands for a tert-butyl group or a benzyl group, and
Z stands for hydrogen or for a saturated or unsaturated, branched or straight-chain C.sub.1 -C.sub.50 alkyl chain, in which the chain or parts of this chain optionally can form a cyclic C.sub.5 -C.sub.8 unit or a bicyclic C.sub.10 -C.sub.14 unit, which contains 0 to 10 oxygen and/or 0 to 2 sulfur atoms and/or 0 to 3 carbonyl, 0 to 1 thiocarbonyl, 0 to 2 imino, 0 to 2 phenylene, 0 to 1 3-indole, 0 to 1 methyl-imidazol-4-yl and/or 0 to 3 N-R.sup.3 groups and is substituted by 0 to 2 phenyl, 0 to 2 pyridyl, 0 to 5 R.sup.2 O, 0 to 1 HS, 0 to 4 R.sup.2 OOC, 0 to 4 R.sup.2 OOC-C.sub.1-4 alkyl and/or 0 to 1 R.sup.2 (H)N groups in which optionally present aromatic groups can be substituted zero to five times, independently of one another, by fluorine, chlorine, bromine, iodine, R.sup.2 OC, 4 R.sup.2 OOC-C.sub.1-4 alkyl, R.sup.2 (H)N, R.sup.2 NHOC, R.sup.2 CONH, O.sub.2 N, R.sup.2 O, R.sup.2 groups, and in which PA1 R.sup.2 stands for hydrogen or a branched or unbranched C.sub.1 -C.sub.4 alkyl radical,characterized in that a compound of general formula II ##STR3## in which R.sup.1 has the above-indicated meaning, is reacted with a carboxylic acid ester of general formula III ##STR4## PA1 T.sup.1 stands for a straight-chain or branched C.sub.1 -C.sub.6 alkyl group, a benzyl, trimethylsilyl, triisopropylsilyl, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy group or a metal ion equivalent of an alkali or alkaline-earth element, in which T.sup.1 is always different from R.sup.1, and PA1 Nu stands for a nucleofuge PA1 D represents, e.g., the benzyloxycarbonyl, BOC, CF.sub.3 CO, Cl.sub.3 CCO or the trityl group PA1 1. The compounds can be coupled by the free acid group regioselectively to functional radicals. As mines in this case, monoamines, oligoamines and polyamines are possible (e.g., octadecylamine, 1,3,6,9 tetraazacyclododecylamine, polylysine or insulin). After cleavage of groups R.sup.1, the DTPA amides that have developed can be used as complexing agents for the production of x-ray, NMR and radiodiagnostic agents or radiotherapeutic agents. The selection of possible radical R.sup.1 makes possible a cleavage under mild (acid or neutral) conditions. In this way, sensitive conjugates can be formed with peptides, hormones or antibodies. PA1 2. After cleavage of groups R.sup.1, the complexing agents that have developed can also be used as an antidote for detoxification with inadvertent incorporation of heavy metals and/or their radioactive isotopes. Here, they are used in the form of free complexing agents and/or the salts of the complexing agents with physiologically compatible cations. PA1 3. After cleavage of groups R.sup.1, the complexing agents that have developed can also be used directly for the production of x-ray, NMR and radiodiagnostic agents or radiotherapeutic agents.
in which Z' has the meaning of an optionally protected group Z, in which Z has the above-indicated meaning and
and then, by cleavage of group T.sup.1 as well as of protective groups optionally contained in Z', the free acid of general formula I is produced, is surprisingly excellently suited to overcome the drawbacks of the known processes.
The invention therefore relates to the process for the production of compounds of general formula I.
The designations of terminal or central carboxylic acids can be defined as follows: ##STR5##
As radicals Z, there can be mentioned as examples the methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, pentyl, hex-3-enyl, heptyl, octyl, i-octyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl or benzyl radical, as well as radicals of formulas ##STR6##
Radical Z can contain, for example, also a heteroaromatic compound, such as a 3-indole radical and/or a histidine radical.
Preferred radicals Z are the methyl, ethyl, propyl, i-propyl, butyl, i-butyl, .sup.tert -butyl, pentyl, hexyl, cyclohexyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, 2-carboxyethyl, 4-aminobutyl, mercaptomethyl, methylthiomethyl, p-hydroxyphenyl or p-hydroxybenzyl radicals of the phenyl and the benzyl radicals.
The HOOC, H.sub.2 N, HS or HO groups optionally present in Z can in this case be present in protected form. Details of the protective group syntheses are further summarized below.
The reaction of compounds of general formula II with compounds of general formula III according to the invention takes place in polar solvents, such as dimethylformamicle, acetonitrile, tetrahydrofuran, 1,4-dioxane, formanfide, dimethylacetamide, dimethyl sulfoxide, acetone as well as in alcohols, such as, for example, methanol, ethanol, isopropanol, preferably in acetonitrile and dimethylformamide. In the case of preferred bromides and chlorides, catalytic amounts of iodide can be added. To catch the acid that has developed in the alkylation, organic bases, such as, e.g., triethylamine, Hunig base or 1,4diazabicyclooctane (DABCO) or else metal hydrides, for example, sodium hydride or alkali or alkaline-earth hydroxides or their carbonates, are used. Preferably, potassium carbonate is used. The reactions take place at 0.degree.-100.degree. C., preferably between 20.degree. and 60.degree. C. The allcylation reagents described by general formula III are partially commercially available or can be produced from the corresponding carboxylic acids, or .alpha.-hydroxycarboxylic acids in a way known in the literature (see, for example: C. F. Ward, Sot., 121:1164 (1922)).
The subsequent release and isolation of the compounds of general formula I takes place in that the intermediately occurring compound of general formula Ia ##STR7## in which R.sup.1 and T.sup.1 have the above-indicated meaning and Z.sup.1 has the meaning of an optionally protected group Z, in which Z has the above-indicated meaning, is converted by cleavage of group T.sup.1 as well as of the protective groups optionally contained in Z to the compound of general formula I. Preferred radical T.sup.1 is the benzyl radical, if R.sup.1 stands for a tert-butyl group.
The cleavage of protective group T.sup.1 as well as the cleavage of the protective groups optionally contained in Z' (conversion of radical Z' to Z) from compounds of general formula Ia takes place according to the processes known to one skilled in the art, such as, for example, by hydrolysis, hydrogenolysis, acid or alkaline saponification of the esters in aqueous-alkaline medium, and optionally solubilizers, such as alcohols, preferably methanol, ethanol, isopropanol or ethers, such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, can be added. As a base, alkali or alkaline-earth hydroxides (such as, e.g., lithium hydroxide, sodium hydroxide or barium hydroxide) or alkali or alkaline-earth carbonates (such as, e.g., potassium carbonate and cesium carbonate) can be used. Preferred temperatures are 0.degree.-100.degree. C., especially 0.degree.-50.degree. C. The subsequent isolation of the compound of general formula I takes place so that it is reacted with ammonium salts, such as, e.g., NH.sub.4 Cl, (NH.sub.4).sub.2 SO.sub.4 or (NH.sub.4).sub.3 PO.sub.4 or the salts are converted to free acids with acid ion exchanger.
Also, the use of diluted citric acid or ion exchangers in H.sup.+ form has proven itself for the release of the acid group from the alkali or alkaline-earth salts.
The acid saponification is performed with mineral acids, such as, e.g., hydrochloric acid, sulfuric acid or else also organic acids (e.g., trifluoroacetic acid) at temperatures of 0.degree.-100.degree. C., preferably 0.degree.-50.degree. C., in the case of trifluoroacetic acid between 0.degree.-25.degree. C. The cleavage of silyl esters takes place with the help of fluoride ions.
The hydrogenolytic cleavage of benzyl derivatives takes place by using the palladium catalysts known to one skilled in the art, preferably 10% palladium on activated carbon or Pearlman's catalyst Pal(OH).sub.2 on carbon. Homogeneous catalysts of the Wilkinson catalyst type can also be used. The hydrogenation is performed in alcohols, such as methanol, ethanol or isopropanol, but preferably isopropanol at temperatures between 10.degree.-50.degree. C., but preferably at room temperature and normal pressure.